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N-terminal Half of Transportin SR2 Interacts with HIV Integrase.

N-terminal Half of Transportin SR2 Interacts with HIV Integrase.
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Tsirkone VG, Blokken J, De Wit F, Breemans J, De Houwer S, Debyser Z, Christ F, Strelkov SV,


Tsirkone VG, Blokken J, De Wit F, Breemans J, De Houwer S, Debyser Z, Christ F, Strelkov SV, (click to view)

Tsirkone VG, Blokken J, De Wit F, Breemans J, De Houwer S, Debyser Z, Christ F, Strelkov SV,

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The Journal of biological chemistry 2017 03 29() pii 10.1074/jbc.M117.777029

Abstract

The karyopherin transportin SR2 (TRN-SR2, TNPO3) is responsible for shuttling specific cargoes such as serine/arginine-rich splicing factors from the cytoplasm to the nucleus. This protein plays a key role in HIV infection by facilitating the nuclear import of the pre-integration complex (PIC) which contains the viral DNA as well as several cellular and HIV proteins including the integrase. The process of nuclear import is considered to be the bottleneck of the viral replication cycle and therefore represents a promising target for anti-HIV drug design. Previous studies have demonstrated that the direct interaction between TRN-SR2 and HIV integrase predominantly involves the catalytic core domain (CCD) and the C-terminal domain (CTD) of the latter. We aimed at providing a detailed molecular view of this interaction through a biochemical characterization of the respective protein complex. Size-exclusion chromatography was used to characterize the interaction of TRN-SR2 with a truncated variant of HIV-1 integrase including both the CCD and CTD. These experiments indicate that one TRN-SR2 molecule can specifically bind one CCD-CTD dimer. Next, the regions of the solenoid-like TRN-SR2 molecule that are involved in the interaction with integrase were identified using AlphaScreen binding assays, revealing that the integrase interacts with the N-terminal half of TRN-SR2 principally through the HEAT repeats 4, 10 and 11. Combining these results with small-angle X-ray scattering data for the complex of TRN-SR2 with truncated integrase we propose a molecular model of the complex. We speculate that nuclear import of the PIC may proceed concurrently with the normal nuclear transport.

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